doença hepática na gravidez

8/8/2019 doena heptica na gravidez

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594 www.thelancet.com Vol 375 February 13, 2010

Liver disease in pregnancy

Deepak Joshi, Andra James, Alberto Quaglia, Rachel H Westbrook, Michael A Heneghan

Severe liver disease in pregnancy is rare. Pregnancy-related liver disease is the most frequent cause of liverdysfunction in pregnancy and provides a real threat to fetal and maternal survival. A rapid diagnosis differentiatingbetween liver disease related and unrelated to pregnancy is required in women who present with liver dysfunctionduring pregnancy. Research has improved our understanding of the pathogenesis of pregnancy-related liverdisease, which has translated into improved maternal and fetal outcomes. Here, we provide an overview of liverdiseases that occur in pregnancy, an update on the key mechanisms involved in their pathogenesis, and assessmentof available treatment options.

IntroductionAlterations in normal physiological and hormonalprofiles occur throughout pregnancy. Moreover, changes

in liver biochemical profile are normal in pregnancy.However, up to 3% of all pregnancies are complicated byliver disorders.1 Severe liver disease, although rare, canoccur and leads to increased morbidity and mortality forboth mother and newborn infant. Liver disorders wereonce thought to be trimester specific, but this is notalways the case. As such, liver disease in pregnancy canbe related or unrelated to pregnancy. Liver diseaseunrelated to pregnancy can be further classified into pre-existing disorders that might become active duringpregnancy and those co-incident with pregnancy. Panel 1lists these liver diseases.

Normal physiological changes in pregnancyA rise in maternal heart rate, cardiac output, togetherwith a fall in blood pressure and systemic vascularresistance, all occur during pregnancy. These alterationsmimic physiological changes in patients withdecompensated chronic liver disease. Blood volumeincreases by about 50%, peaking in the second trimester.However, blood flow to the liver remains constant andthe liver usually remains impalpable during pregnancy.Telangiectasia or spider angiomas and palmar erythemaare normal findings in pregnancy and are caused by thehyperoestrogenic state. Gall bladder motility is decreased,which increases the lithogenicity of the bile.

During a normal pregnancy, serum albumin con-

centration falls due to the expansion in plasma volume,and the alkaline phosphatase activity increases due toadded placental secretion (table 1). In general, amino-transferase concentrations (alanine aminotransferaseand aspartate aminotransferase), bilirubin, and gamma-glutamyl transpeptidase all remain normal throughoutpregnancy, and their change should be furtherinvestigated. On light microscopy, the liver appearsnormal or near normal.2

Ultrasonography remains the safest imaging modalityto visualise the liver during pregnancy. However, iffurther detailed imaging is needed, MRI without contrastis safe. Gadolinium-enhanced MRI should be avoidedbecause of transplacental transfer and unknown effectson the fetus.3

Pregnancy-related liver diseasesHyperemesis gravidarumNausea and vomiting are not uncommon in pregnancy.

Hyperemesis gravidarum occurs in 0320% of allpregnancies usually within the first trimester.4,5 Under-reporting of symptoms of this condition might accountfor the variation of the reported incidence in publishedreports. One of the most frequently used definitions ofhyperemesis gravidarum is that of intractable vomiting,resulting in dehydration, ketosis, and weight loss of 5%or more. The cause remains unclear but abnormal gastricmotility, hormonal factors, and changes in the autonomicnervous system are all probably involved. Risk factorsinclude increased body-mass index (BMI), psychiatricillness, molar pregnancy, pre-existing diabetes, andmultiple pregnancies.6,7 Hyperthyroidism is seen in an

estimated 60% of cases of hyperemesis gravidarum

8,9

andmight occur because of high serum concentrations ofhuman chorionic gonadotropin, which has increasedthyroid-stimulating activity during pregnancy.9

Hyperemesis gravidarum can start as early asweek 4 of gestation and typically resolves by week 18.Serum aminotransferases can be raised by as much as20 times the upper limit of normal, but jaundice is rare(table 2).10 Other biochemical abnormalities includeraised serum urea and creatinine concentrations, hypo-phosphataemia, hypomagnesiumia, and hypokalaemia.Biochemical abnormalities resolve on resolution ofvomiting. Persistent abnormalities of the liver shouldalert the physician to alternative diagnoses (ie, viral

hepatitis). Liver biopsy is not indicated, but when done,it shows non-specific changes including mild steatosis

Search strategy and selection criteria

We searched Medline (from January, 1966, to present)

for publications containing the terms liver disease in

pregnancy in combination with jaundice and

transplantation. We selected publications mainly from the

past 5 years, but did not exclude seminal older publications.

We also reviewed reference lists of publications identified by

this search strategy and selected those we judged relevant.

Our reference list was modified on the basis of comments

from peer reviewers.

Lancet 2010; 375: 594605

Institute of Liver Studies,

Kings College Hospital,

London, UK (D Joshi MRCP,

A Quaglia FRCPath,

R H Westbrook MRCP,

M A Heneghan MD); and

Department of Maternal-Fetal

Medicine/Obstetrics and

Gynaecology, Duke University

Medical Centre, Durham, NC,

USA (A James MD)

Correspondence to:

Dr Michael A Heneghan, Instituteof Liver Studies, Kings College

Hospital, Denmark Hill,

London SE5 9RS, UK

[email protected]


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www.thelancet.com Vol 375 February 13, 2010 595

and cholestasis.2 Persistent symptoms beyond week 18

should warrant consideration of a gastroscopy toexclude mechanical obstruction.Treatment of hyperemesis gravidarum is supportive

and includes intravenous rehydration, antiemetics, andgradual reintroduction of oral intake. Vitaminsupplementation, especially thiamine, is mandatory toprevent Wernickes encephalopathy. Most patients willneed 58 days of hospital admission, but relapseis common. No benefit in outcomes is seen with theuse of steroids.11 Recurrence in subsequent pregnanciesis common.

Intrahepatic cholestasis of pregnancyIntrahepatic cholestasis is defined as pruritus with

elevated serum bile acids occurring in the second half ofpregnancy, which resolves after delivery.12 Recurrence insubsequent pregnancies is common. The incidence inEurope ranges from 01% to 15% of pregnanciescompared with a much higher incidence in Scandinaviaand South America.12,13 Maternal morbidity is low andtherefore the importance of this disorder is related to itseffects on the fetus. Intrahepatic cholestasis can lead tochronic placental insuffi ciency, resulting in fetalcomplications that include anoxia, prematurity, perinataldeath, fetal distress, and stillbirth.14 Risk factors includewomen who develop cholestasis secondary to the oralcontraceptive pill and a family history of the condition.

The cause of intrahepatic cholestasis remains unclearbut is related to abnormal biliary transport across thecanalicular membrane. Direct effects of female sexhormones induce cholestasis and inhibit the bile saltexport pump. Mutations in the bile salt export pumphave been implicated in the pathogenesis of intrahepaticcholestasis.15,16 The multidrug resistance protein 3(MDR3) is the key transporter for phospholipids acrossthe canalicular membrane (figure 1). Mutations in thisgene lead to loss of function and thus increased serumbile acids.18 The MDR3 mutation is located onchromosome 7q21.1 and has been identified in 15% ofcases of intrahepatic cholestasis.17 Overall, ten differentmutations have been identified.18,19 Floreani and

colleagues19 found that only heterozygous mutationscause transporter dysfunction, whereas completeabsence of transport function is associated with severeliver disease.

The key symptom is pruritus, especially of the palmsand soles, which is followed by generalised symptoms,and this usually occurs from week 25 of gestation.Jaundice is uncommon, but when present, arises24 weeks after the onset of pruritus. Aminotransferaseactivity can be increased by 20 times the normal level.Raised gamma-glutamyl transferase activity is unusualbut is indicative of MDR3 mutation or underlying liverdisease unrelated to pregnancy. The key diagnostic test isa fasting serum bile acid concentration of greater than10 mol/L.14 Prospective studies have shown that fetal

complications correlate with serum bile acidconcentrationsthe risk being inexistent if levels remainbelow 40 mol/L.14,20 Patients can also develop diarrhoeaand steatorrhoea requiring fat soluble vitaminsupplementation. Liver biopsy is not needed. Histologicalfindings consist of perivenular canalicular cholestasiswith preserved portal tracts.

Early recognition and diagnosis of intrahepaticcholestasis with a multidisciplinary approach in-corporating hepatological support is important. Womenbefore weeks 3334 of pregnancy should be referred toobstetric centres with appropriate facilities for high-riskpremature newborn infants.

Alteration from non-

pregnant state

Haemoglobin (118148 g/L) from second trimester

White cell count (39111109/L)

Platelets (150450109/L) None

Packed cell volume (036044 L/L)

Prothrombin time (1012 s) None

Alkal ine phosph atase (42128 IU/L) (bo ne and placenta)

Albumin (3550 g/L)

ALT (070 IU/L) None

GGT (235 IU/L) None

Bilirubin (017 mol/L) None

Alpha-fetoprotein (044 g/L)

Cholesterol (355 mmol/L)

Uric acid (160395 mol/L)

=increase. =decrease. ALT=alanine aminotransferase. GGT=gamma-glutamyl

transpeptidase.

Table 1: Biochemical changes during normal pregnancy

Panel 1: Classification of liver diseases in pregnancy

Pregnancy-related liver diseases

Hyperemesis gravidarum

Intrahepatic cholestasis of pregnancy

Pre-eclampsia and eclampsia

HELLP syndrome

Acute fatty liver of pregnancy

Pregnancy-unrelated liver diseases

Pre-existing liver diseases

Cirrhosis and portal hypertension

Hepatitis B and C

Autoimmune liver disease

Wilsons disease

Liver diseases co-incident with pregnancy Viral hepatitis

Biliary disease

Budd-Chiari syndrome

Liver transplantation

Drug-induced hepatotoxicity

HELLP=haemolysis, elevated liver enzymes, and low platelets.


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Ursodeoxycholic acid decreases plasma bile acid andsulphated progesterone metabolite concentrations.Studies have also shown that it increases bile salt exportpump (ATPB11, MDR3, and MRP4) expression.21Ursodeoxycholic acid (1015 mg/kg bodyweight) providesrelief against pruritus, improve liver function tests, andis well tolerated both by mother and fetus.22 Improvementin pruritus might be associated with decreased urinaryexcretion of progesterone metabolites specific forintrahepatic cholestasis of pregnancy.23 Glantz andcolleagues20 showed that ursodeoxycholic acid is moreeffective in alleviating pruritus than is dexamethasone

(p=001) in patients with bile acid concentrations greaterthan 40 mol/L. When delivery is being considered in apreterm fetus, the administration of dexamethasone alsopromotes fetal lung maturity. Cholestyramine can also beused, but is not very effective at decreasing serum bileacid concentrations and can exacerbate vitamin Kdeficiency.

Intrahepatic cholestasis of pregnancy normally resolvesafter delivery but, in rare cases of familial forms, thecondition can persist after delivery, leading to fibrosisand even cirrhosis.24 In these cases, an increased risk ofcholestatic liver disease exists, irrespective of pregnancy.Intrahepatic cholestasis of pregnancy might therefore bea predictor for the development of liver and biliary diseasein the future.24

Hypertension-related liver diseases and pregnancy

Hypertension in pregnancy is defined as a blood pressuregreater than 140/90 mm Hg on at least two occasions.Pre-eclampsia, eclampsia, HELLP (haemolysis elevatedliver enzymes and low platelets) syndrome, hepaticinfarction, and rupture are all related to hypertension inpregnancy.

Pre-eclampsia and eclampsiaPre-eclampsia is a multisystem disorder affecting510% of all pregnancies and can involve the kidneys,the CNS, the haematological system, and the liver. Pre-eclampsia is characterised by hypertension andproteinuria (greater than 300 mg in 24 h) after 20 weeksof gestation and/or within 48 h after delivery. Oedema

is no longer needed for the diagnosis of pre-eclampsia.25Presence of seizures differentiates eclampsia from pre-eclampsia. Atypical pre-eclampsia is the occurrence ofthe signs, symptoms, and the biochemical abnormalitiesof pre-eclampsia but without hypertension orproteinuria. Risk factors for pre-eclampsia includeextremes of maternal age (45 years),primiparity, pre-existing hypertension, family history,and occurrence in a previous pregnancy. Placentalischaemia, leading to endothelial dysfunction andcoagulation activation, is thought to be important.26Genetic predisposition and imbalance of prostacyclinand thromboxane have also been implicated in thepathogenesis of pre-eclampsia.27

Clinical features include right upper abdominal pain,headache, nausea, and vomiting. Abnormal liver functiontests, which are thought to be secondary to vaso-constriction of the hepatic vascular bed, occur in 2030%of patients. Aminotransferase activity could be as highas ten times the upper limit of normal, whereas bilirubinconcentrations are rarely increased. Liver biopsy is notindicated. Characteristic microscopic changes (figure 2)involve periportal areas with identifiable sinusoidalfibrin thrombi, haemorrhage, and hepatocellularnecrosis. Portal thrombosis and haemorrhage can alsobe present.Tight control of blood pressure is essential,but liver involvement, albeit infrequent, suggests severe

disease, thus alerting the physician that immediatedelivery is necessary. Complications include maternalhypertensive crises, renal dysfunction, hepatic ruptureor infarction, seizures, and increased perinatal morbidityand mortality. Liver biochemical profile usuallynormalises within 2 weeks of delivery.

HELLP syndromeThe combination of haemolysis with a micro-angiopathicblood smear, increased liver enzymes, and low platelets(HELLP) in pregnancy was first described in 1982 byWeinstein28 and affects six in 1000 pregnancies. 510% ofwomen with pre-eclampsia develop HELLP.29,30 AlthoughHELLP shows symptoms similar to pre-eclampsia and isone of the criteria that can define severe pre-eclampsia, it

Amino phospho-lipids

Conjugated bilirubin

Glutathione

Phosphatidylcholine

SitosterolCholesterol

Cystic fibrosis

Chloride

Bicarbonate

CFTR (ABCC7)

AE2 (SLC4A2)

Bileduct

Hepatocyte

PFIC2, BRIC2

HCO3

ClCl

Bile acids

DrugsMDR1(ABCB1)

BSEP(ABCB11)

FIC1

(ATP 8B1)

MRP2

(ABCC2)

MDR3(ABCB4)

ABCG5/8

ICP, PFIC3,drug-inducedcholestasis

PFIC1, BRIC1 Dubin-Johnson syndrome

Figure 1: Hepatobiliary transporters

MDR3 translocates phosphatidylcholine across the canalicular membrane. Lack of this phospholipid leads to the

formation of toxic monomeric bile salts in the bile ducts, which in turn results in cholangiocyte injury,

pericholangitis, and periductal fibrosis. Mutations in the MDR3 transporter have been identified in the

pathogenesis of drug-induced cholestasis, PFIC3, and cholestasis of pregnancy. Red dotted arrows show the

phenotype expressed when a mutation occurs in the targeted transporter gene. PFIC1=progressive familial

intrahepatic cholestasis type 1. PFIC2=progressive familial intrahepatic cholestasis type 2. PFIC3=progressive

familial intrahepatic cholestasis type 3. ABCG5/8=ATP binding cassette transporters G5 and G8.AE2=anion

exchanger.BSEP=bile salt export pump. BRIC1=benign recurrent intrahepatic cholestasis type 1. BRIC2=benign

intrahepatic cholestasis type 2. CFTR=cystic fibrosis transmembrane conductance regulator. FIC1=familial

intrahepatic cholestasis type 1. ICP=intrahepatic cholestasis of pregnancy. Cl= chloride ion. HCO3=bicarbonate

ion. MRP2=multidrug resistance-associated protein 2. MDR1=multidrug resistance protein 1. MDR3=multidrug

resistance protein 3. Modified, with permission, from Trauner and colleagues. 17


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can develop in women who might not have any other

signs or symptoms of pre-eclampsia. A perinatal infantmortality rate of 670% has been reported due toprematurity, or secondary to maternal complications.31HELLP usually arises in the second or third trimester,but can also develop after delivery. Risk factors includeadvanced maternal age, multiparity, and white ethnicorigin.

Angiogenic markers have also been identified, whichmight help to confirm the diagnosis of pre-eclampsia inwomen without hypertension or proteinuria. Theyinclude decreased placental growth factor, increasedserum soluble endoglin, and increased soluble fms-liketyrosine kinase-1 (VEGF) receptor.3236

Patients with HELLP syndrome might be asymptomatic

or present with right upper quadrant and epigastricpain, nausea, vomiting, and malaise. Hypertension andproteinuria is evident in up to 85% of cases. Liver injuryis precipitated by intravascular fibrin deposition, hypo-volaemia, and increased sinusoidal pressure resultingin mild-to-moderate increase of aminotransferases andmild elevation of bilirubin. Recognised classificationsystems of HELLP include the Tennessee and theMississippi systems (panel 2).37 In the Tennesseesystem classification, the result can be complete(ie, demonstration of haemolysis [raised lactate dehydro-genase, decreased haptoglobin, raised unconjugatedbilirubin], thrombocytopenia [secondary to vascularendothelial damage and fibrin deposition in vascularwalls], and elevated aminotransferases) or partial(ie, encompassing one or two components). Theprothrombin time or international normalised ratioremains normal unless there is evidence of disseminatedintravascular coagulation or severe liver injury. A serumuric acid of more than 464 mol/L is associated withincreased maternal and fetal morbidity and mortality.20,31Liver biopsy remains a high-risk procedure because ofthe thrombocytopenia. Microscopic findings may benon-specific or similar to those of pre-eclampsia(figure 2).

Hepatic haematoma, infarction, and rupture

CT or MRI of the liver could identify hepatic infarctionand rupture, haemorrhage, or subcapsular haematoma.The differential diagnosis includes acute fatty liver ofpregnancy, thrombotic thrombocytopenic purpura, andhaemolytic uraemic syndrome. Hepatic haematoma,infarction, and rupture occur in a minority of womenwith established pre-eclampsia or HELLP syndrome.50% maternal mortality has been reported for thiscomplication of disease, with prevalence of hepaticrupture being higher with severe thrombocytopenia.38Hepatic adenoma, hepatocellular carcinoma, andhaemangiomas might also rupture during pregnancy.

Risk factors for rupture include advanced maternalage, multiparity, and pre-eclampsia. Patients withhepatic haematoma secondary to a ruptured liver

capsule typically present in the third trimester withsevere right upper quadrant pain and pyrexia, although

the presentation can also be early after delivery.Increased aminotransferase concentrations in excess of3000 U/L, leucocytosis, pyrexia, and anaemia arefrequently seen. Acute complications include acuterespiratory distress syndrome, acute kidney injury, andhypovolaemic shock. CT and MRI help to identify thesepathologies (figure 3). Contained haematomas shouldbe managed conservatively with blood transfusion andsupportive measures for the mother. Infection can occurwithin areas of hepatic infarction. Haemodynamicinstability suggests persistent active bleeding andshould prompt hepatic angiography, and when required,invasive haemostatic measures by arterial embolisationof the hepatic artery or surgical exploration. Surgicaloptions include packing, hepatic artery ligation, or

Panel 2: Classification systems used in HELLP syndrome

Tennessee system

AST >70 IU/L

LDH >600 IU/L

Platelets 40 IU/L and LDH >600 IU/L and:

Class I: platelets


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resection of the affected liver. No long-term maternalcomplications have been reported.

Women with HELLP syndrome might need a high-dependency unit or an intensive care setting because ofthe potential complications of hepatic encephalopathy,acute renal dysfunction, hepatic rupture, and bleeding.The cornerstone of management is delivery. Promptdelivery should be undertaken if pregnancy is over34 weeks of gestation, if fetal distress is present, or ifevidence exists of maternal end-organ disease(ie, disseminated intravascular coagulation, renal failure,or abruptia placenta).39 Management of hypertensioninvolves the use of labetalol, hydralazine, and nifedipine.Diuretics are not recommended in patients with HELLP,

because they can cause uteroplacental hypoperfusion.39

Intravenous magnesium sulphate with platelet,coagulation support, or both, are recommended,especially in the presence of bleeding. If gestation is lessthan 34 weeks, corticosteroids should be administered topromote fetal lung maturity only, because they do notprovide any maternal benefit.40

Women with atypical pre-eclampsia have a morediffi cult diagnostic and management conundrum.Physicians should therefore be vigilant to atypicalpresentations of pre-eclampsia with careful assessmentof maternal risk factors, laboratory findings, and timingin the course of pregnancy.

The risk of recurrence of HELLP syndrome insubsequent pregnancies is increased.41,42 HELLP

syndrome usually resolves rapidly after delivery.Laboratory values, however, might worsen after delivery.Hepatic or renal failure necessitates admission tointensive care. Indications for liver transplantationinclude persistent bleeding from haematoma, hepaticrupture, or liver failure.43 88% of these patients survive5 years after liver transplant.44

Acute fatty liver of pregnancyFirst described in 1934 by Stander and Cadden45 as acuteyellow atrophy of the liver,acute fatty liver of pregnancyremains a medical and obstetric emergency. Thiscondition is defined as microvesicular fatty infiltrationof hepatocytes during the second half of pregnancy(usually third trimester), and it remains a commoncause of liver failure in pregnancy. Maternal and fetalmortality rates are significantly increased and rangebetween 1% and 20%.46

Acute fatty liver of pregnancy is a rare disorder affectingfrom one in 7000 to one in 16 000 pregnancies,47,48therefore making it diffi cult to study. A recent UK-basedprospective study involving 229 centres identified57 confirmed cases in a total of 1 132 964 pregnancies,giving an incidence of five in 100 000 pregnancies. 49 74%of cases were identified at a median gestation age of36 weeks, with 60% of cases delivered within 24 h ofdiagnosis.49 The caesarean section rate was 74%.

Acute fatty liver of pregnancy is one of the mitochondrialcytopathies, which include Reyes syndrome and otherdrug-related liver diseases. Common characteristics ofthese disorders include vomiting, hypoglyacaemia, lacticacidosis, hyperammonaemia, and microvesicular fatdeposition in organs. Abnormality in mitochondrial oxidation is recognised as the cause of this condition.48Mitochondrial oxidation of fatty acids is a complexprocess and is an important energy source for skeletalmuscle and myocardial tissue. The enzyme long-chain3-hydoxyacyl coenzyme A dehydrogenase is part of themitochondrial trifunctional protein (MTP), which is animportant complex associated with the inner mitochondrialmembrane.50,51 MTP is an hetero-octamer consisting offour subunits and four subunits52 (figure 4).

Figure 3: Abdominal CT showing a subcapsular haematoma in a woman with HELLP syndrome

3-ketoacyl-CoA

thiolase

Shortenedacyl-CoA

3-ketoacyl-CoA

3-hydroxyacyl-CoA

Trifunctional protein

2,3-enoyl-CoA

Acyl-CoA

Acyl-CoAdehydrogenase

2,3-enoyl-CoAhydratase

3-hydroxyacyl-CoAdehydrogenase

LCHAD deficiency

Tri-functionalproteindeficiency

Figure 4: Cycle of mitochondrial oxidation

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) catalyses the third step in the oxidation of fatty acids in

mitochondria (the formation of 3-ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation of long-chain

3-hydroxyacyl metabolites produced by the fetus or placenta is toxic to the liver. LCHAD deficiency in infants can

lead to non-ketotic hypoglycaemia, hepatic encephalopathy, cardiomyopathy, peripheral neuropathy, myopathy,

and sudden death. Modified, with permission, from Ibdah and colleagues.53


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Ibdah and colleagues53 showed that sick infants born to

mothers with acute fatty liver of pregnancy with featuresof HELLP syndrome had defects in fatty acid oxidationand were deficient in the long-chain 3-hydoxyacylcoenzyme A dehydrogenase predominately because ofthe Glu47G1n mutation on one or both alleles ofthe subunit of the trifunctional protein.53 Long-chain3-hydoxyacyl coenzyme A dehydrogenase deficiency inthe fetus was associated with a 79% chance of developingeither acute fatty liver of pregnancy or HELLP syndrome.53Other studies have identified the association between thelong-chain 3-hydoxyacyl coenzyme A dehydrogenasedeficiency, especially the G1528C mutation on one orboth alleles, and acute fatty liver of pregnancy.54 A 20-foldincreased risk of development of maternal liver disease

during pregnancy is present in fetuses with fatty acidoxidation defects compared with those without thedefect.55 Fetal fatty acids accumulate and return to thematernal circulation. These long-chain fatty acids aredeposited in the liver, thus causing liver toxicity.

Clinical presentation of acute fatty liver of pregnancyvaries from nausea and abdominal pain to hepaticencephalopathy and jaundice. Risk factors include twinpregnancies and nulliparity. Knight and colleagues49identified that an inverse relation may exist between BMIand acute fatty liver of pregnancy, in contrast to the directassociation between BMI in pre-eclampsia.56,57Disseminatedintravascular coagulation can occur with normal hepaticlaboratory findings, but common abnormalities includeraised aminotransferase concentrations, prothrombintime, and serum uric acid and bilirubin concentrations.Hypoglycaemia is a poor prognostic sign. Serum ammoniaconcentration rise and lactic acidosis are present in severedisease. Evidence of renal dysfunction is common.Leucocytosis occurs in 98% of patients.49 Differentialdiagnosis includes HELLP syndrome and viral hepatitis.Ultrasonography and computed tomography might beinconsistent at detecting fatty infiltration.58 Viral serology ismandatory in every case.

Although the gold standard for diagnosis is liver biopsy(figure 5), this is rarely necessary. The characteristicmicroscopic change is microvescicular steatosis, which

can be in the form of minute cytoplasmic vacuoles ordiffuse cytoplasmic ballooning that might spare theperiportal hepatocytes. This latter change might simulatehepatocyte ballooning of other causes. Canalicularcholestasis is also present. Necrosis of individual orgroups of hepatocytes replaced by ceroid-ladenmacrophages might be present. Extra-medullaryhaemopoiesis might also be present.2 These changesdisappear within days to weeks after delivery withoutpersistent injury. The Swansea diagnostic criteria are analternative to liver biopsy (panel 3).

Prompt delivery is essential in women with acute fattyliver of pregnancy. Steroids might be needed for lungmaturation in preterm fetuses. After delivery, womencan develop a long cholestatic phase, taking up to 4 weeks

for resolution. Liver transplantation warrants con-sideration in cases of severe hepatic encephalopathy, liverrupture, and in case of failure of recovery of liver function.The newborn infant should be assessed for signs ofhypoglycaemia, hepatic failure, myopathy, and otherfeatures associated with defects in fatty acid oxidation.

An increased recurrence rate has only been reportedin women who carry the long-chain 3-hydoxyacylcoenzyme A dehydrogenase mutations.54 However,recurrent acute fatty liver of pregnancy might also re-occur in women without detectable mutations.59 Infantsborn to mothers with acute fatty liver of pregnancy shouldbe screened for defects of fatty acid oxidation. Womencan, however, be reassured that chronic liver disease doesnot develop in acute fatty liver of pregnancy.

Pre-existing liver diseases and pregnancy

Cirrhosis with portal hypertensionPregnancy in cirrhotic women is rare.60 Cirrhosis leads toanovulation and amenorrhoea due to many factors thatinclude disturbed oestrogen and endocrine metabolism.61,62When pregnancy is successful in a cirrhotic woman,spontaneous abortion rate, risk of prematurity, andperinatal death rate are all increased.63 Cirrhotic patientshave a high risk of liver decompensation because ofworsening synthetic liver function, development of ascites,and hepatic encephalopathy.63 Maternal mortality rate ashigh as 105% has been described in this group.64Maternalprognosis depends on the degree of hepatic dysfunctionduring pregnancy rather than its cause.46 Portalhypertension worsens during pregnancy because ofincreased blood volume and flow. Portal pressures can

Figure 5: Acute fatty liver of pregnancy

Haematoxylin and eosin staining. Hepatocytes show a clear cytoplasm (arrow) or many minute vacuoles

(arrowhead) consistent with steatosis. In the inset, the appearance of conventional macrosteatosis as seen in

steato-hepatitis.


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also increase because of an increased vascular resistancedue to external compression of the inferior vena cava bythe gravid uterus. Up to 25% of patients with varices havea bleeding episode during pregnancy.65 The greatest risk isseen in the second trimester, when portal pressures peak,and during delivery because of the repeated use of thevalsalva manoeuvre to help to expel the fetus.64 Rupture ofsplenic artery aneurysm, although uncommon, could alsopresent in pregnant women with portal hypertension.

All cirrhotic patients should undergo variceal screening.Banding before pregnancy, although not proven, isappropriate for high-risk varices. Propranolol has alsobeen used safely in pregnancy but side-effects includefetal growth retardation, neonatal bradycardia, andhypoglycaemia. Terlipressin has not been studied inpregnancy but concerns have been raised about decreasedplacental perfusion and increased risk of placentalabruption. The use of a transjugular intrahepatic porto-systemic shunt in extreme cases of variceal bleeding can

be considered but has the risk of radiation exposure tothe fetus.

Hepatitis B and hepatitis C infectionsIn many developed countries, pregnant women areroutinely screened for hepatitis B virus (HBV) at theinitial booking visit.66 HBV vaccine can be given safelyduring pregnancy if needed.67 Women who are notcirrhotic but HBV-positive are at risk of transmitting thevirus to the fetus. Vertical transmission remains the mostcommon way of transmission of HBV in endemic areasand accounts for most HBV infection worldwide. ChronicHBV infection is more likely in the newborn infant whenthe mother is positive to both hepatitis B surface antigenand hepatitis B e antigen, and also has a high HBV viral

load. HBV viral load is a key factor in transmission, with

high viral load being associated with 8090% risk oftransmission compared with 1030% transmission ratesin patients with undetectable viral load.68,69 Transmissioncan occur directly via the placenta (intrauterine), duringbreastfeeding, or during delivery. Mode of delivery doesnot affect the risk of transmission, with similar rates seenwith normal vaginal delivery and caesarean section.70Transmission can be reduced further by administrationof hepatitis B immunoglobulin to the neonate within 12 hof birth.71 HBV vaccine should also be administered, withthree doses being given to the infant within the first6 months.

Use of lamivudine and other antiviral drugs during thethird trimester to reduce HBV viral load, 72 and thus

decrease the risk of transmission to the fetus, is a sourceof debate. Use of lamivudine monotherapy couldpredispose to viral mutations, thus rendering the patientsusceptible to viral resistance to both lamivudine andother antiviral drugs long term. Lamivudine, which hasbeen classified by the US Food and Drug Administration(FDA) as a category C drug in pregnancy, has been usedsuccessfully in patients with both HBV and HIV infectionduring pregnancy without substantial risk to eithermother or fetus. Entecavir, a more potent nucleosideanalogue with a better long-term viral resistance profilethan lamivudine, and designated as a category C drug inpregnancy by the FDA, also shows promise, whereastenofovir, widely used in HIV-positive pregnant patients,seems to have a better safety profile than both entecavirand lamivudine, and is regarded as a category B drug.

At present, no guidelines exist for the use of lamivudineor any other nucleoside in HBV-positive pregnantwomen, and therefore any decisions should be made onan individual basis. We advise the use of eitherlamivudine or tenofovir after week 32 of gestation inpatients with a high HBV viral load (greater than10 copies per mL), especially in mothers who mighthave already infected their child during their previouspregnancy. However, the duration of therapy needs to beconsidered carefully. Moreover, the use of antiviralagents should not be a substitute to appropriate

vaccination.Pregnancy in patients with hepatitis C virus (HCV) is

usually uneventful. Risk of vertical transmission of HCVremains low, except when the fetus is exposed to largevolumes of mothers blood and vaginal fluid duringdelivery or if the mother is co-infected with HIV.73,74Patients with genotypes 1 or 3 and with HIV co-infectionare more likely to transmit HCV vertically.75 Ribavirin isteratogenic and the use of pegylated interferon incombination with ribavirin is contra-indicated duringpregnancy, but not during breastfeeding.

Autoimmune liver diseaseSuccessful pregnancies are achievable in women withautoimmune hepatitis. Some studies have shown that

Panel 3: Swansea diagnostic criteria for diagnosis of acute

fatty liver of pregnancy1

Six or more of the following features in the absence of

another explanation

Vomiting

Abdominal pain

Polydipsia/polyuria

Encephalopathy

High bilirubin (>14 mol/L)

Hypoglycaemia (340 mol/L)

Leucocytosis (>11106/L)

Ascites or bright liver on ultrasound scan

High AST/ALT (>42 IU/L)

High ammonia (>47 mol/L) Renal impairment (creatinine >150 mol/L)

Coagulopathy (PT >14 s or APTT >34 s)

Microvesicular steatosis on liver biopsy

ALT=Alanine aminotransferase. AST=aspartate aminotransferase. PT=prothrombin

time. APTT=activated partial thromboplastin time.


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flares in disease activity are more likely to occur in the

first 3 months after delivery, although autoimmunehepatitis might present for the first time duringpregnancy.76,77 Women with autoimmune hepatitis needstable immunosuppression throughout pregnancy.Although azathioprine is teratogenic in animal models,teratogenic effects in human beings have not beendescribed. Two separate studies failed to show toxiceffects of azathioprine or its metabolites duringpregnancy.76,77 Fetal side-effects have been reported,however, and include lymphopoenia, hypogam-maglobulinaemia, and thymic hypolasia. If flares occur,then they should be managed in the conventionalmannerthat is, administration of steroids or increasein steroid dose. If an immunosuppressant is needed,

azathioprine remains the safest choice. A study76described the presence of antibodies to SLA/LP andRo(SSA) as risk factors for adverse outcomes inpregnancy.

Primary biliary cirrhosis is a chronic cholestatic diseasethat leads to destruction of intrahepatic bile ducts.Deterioration in synthetic liver function can occur duringpregnancy.78 Primary biliary cirrhosis might also presentfor the first time after delivery with protracted pruritus.Ursodeoxycholic acid can be used safely in pregnantwomen with primary biliary cirrhosis.78

Wilsons diseaseWilsons disease is a rare autosomal recessive disease ofdefective biliary copper excretion, which leads to copperdeposition in the liver, brain, and kidneys. Patientsusually present with hyperbilirubinaemia, high con-centrations of aminotransferases, Coombes-negativehaemolytic anaemia, and low serum alkaline phosphatase.In pregnant women with undiagnosed Wilsons disease,evidence of acute liver failure and haemolysis could bemisinterpreted as HELLP syndrome.

In women with known Wilsons disease, serum copperlevels and caeruloplasmin can rise during pregnancy79without treatment, leading to a flare in patient symptoms.Zinc can be continued in pregnancy without causingharm to the fetus.80

Liver diseases co-incident with pregnancyAcute viral hepatitisHepatitis A virus (HAV) infection in pregnancy has aclinical course similar to that in the non-pregnantpopulation.81 A recent study has identified the presenceof ascites and hypertension as factors that help todifferentiate liver disease specific to pregnancy from viralhepatitis.82 Increased severity of disease is associated withadvanced maternal age, with severe infection in the thirdtrimester associated with an increased risk ofprematurity.83 Treatment is supportive.

Pregnant women are more vulnerable to hepatitis Evirus (HEV) infection than to HAV, HBV, and HCV. 84HEV remains the most prevalent viral cause of acute

liver failure in pregnancy.85 Endemic in parts of Asiaand Africa, HEV-related hepatitis usually follows a moresevere course in pregnancy, especially in the Indiansubcontinent,8688 with these patients more likely todevelop fulminant hepatic failure.89 In-utero trans-mission of HEV to the fetus might add further toxicmetabolites to the maternal circulation,90,91 resulting inincreased maternal morbidity and mortality.92 Pregnantwomen are more likely to acquire HEV in the second orthird trimester, with a median gestational age of28 weeks.86 Reported maternal mortality from fulminanthepatic failure secondary to HEV in pregnancy is

Trimester Diagnosti cs

HG 1, 2 Bilirubin (4 ULN), ALT/AST (24 ULN)

ICP 1, 2, 3 Bilirubin (6 ULN), ALT/AST (6 ULN), bile acids

Pre-eclampsia 2, 3 Bilirubin (25 ULN), ALT/AST (1050 ULN), platelets

HELLP 2, 3 ALT/AST (1020 ULN), LDH, platelets, uric acid

AFLP 2, 3 Bilirubin (6-8 ULN), ALT/AST (510 ULN)rarely >20

=increase. =decrease. HG=hyperemesis gravidarum. ICP=intrahepatic cholestasis of pregnancy. HELLP=haemolysis,

elevated liver enzymes, and low platelets. AFLP=acute fatty liver of pregnancy. ALT=alanine aminotransferase.

AST=aspartate aminotransferase. LDH=lactate dehydrogenase. ULN=upper limit of normal.

Table 2: Characteristic timings and diagnostic laboratory features of liver diseases related topregnancy

Figure 6: Percutaneous transhepatic cholangiogram showing large choledochal cystsTwo large choledochal cysts (arrows) in a patient who had previously undergone biliary reconstruction due to

repeated bouts of biliary sepsis.


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4154%,82,93 with a fetal mortality rate of 69%. 75 Pooroutcomes are associated with the development ofgrade III or IV hepatic encephalopathy,75 irrespective ofwhich trimester the infection was contracted. Manage-ment is supportive, ideally including intensive care unitinput. Remarkably, delivery does not affect maternaloutcome.

Herpes simplex virus (HSV) hepatitis is a rarecondition, occurring predominantly in immuno-compromised individuals or children.94,95 Pregnantwomen, however, are more susceptible than the generalpopulation to HSV hepatitis,96 with a 39% maternalmortality. HSV serotypes 1 and 2 have been seen inpregnancy and are caused by primary or latent disease.Raised aminotransferases, thrombocytopenia, leuco-penia, and coagulopathy with a normal concentration ofserum bilirubin are common laboratory findings.Mucocutaneous lesions associated with HSV infectionmight be present, but only in 50% of cases. 97 HSVhepatitis should be considered in any pregnant womanwith hepatic failure. Liver biopsy provides the definitiveevidence of HSV hepatitis, but computed tomographycould also be useful, showing multiple low-density areasof necrosis within the liver. Treatment with intravenousaciclovir should not be delayed until confirmatory

results are available, and should therefore be commencedif clinical suspicion is high. Treatment with aciclovir isassociated with improved survival rate.96 Publishedreports of this rare disease are unclear as to whetherdelivery improves neonatal survival.

Biliary diseaseGallstones are more common in pregnancy because ofincreased cholesterol secretion in the second and thirdtrimester, increased lithogenicity of the bile, anddecreased gallbladder motility.98 About 10% of pregnantwomen develop either gallstones or viscus biliarysludge.99 Open or laparoscopic cholecystectomy can bedone safely and successfully during the second trimester.Endoscopic retrograde cholangiopancreatography and

sphincterotomy can be done if needed, with little added

risk compared with that in non-pregnant women.

100

Choledochal anomalies (figure 6) might also present inpregnancy, as a consequence of bile stasis and stoneformation. Septic episodes can ensue.

Budd-Chiari syndromeBudd-Chiari syndrome is defined as outflow obstructionof the hepatic veins. It is commonly associated withmyeloproliferative disorders. Up to 20% of cases ofBudd-Chiari syndrome occur in women who are on theoral contraceptive pill, are pregnant, or have delivered inthe previous 2 months.101 Pregnancy itself represents aprothrombotic state; a physiological decrease ofprotein S concentration is seen,102 which might account

for the increased incidence of Budd-Chiari syndrome inpregnancy.103 Patients with known Budd-Chiari syndromeare at risk of developing an exacerbation duringpregnancy because of the increased concentrations offemale sex hormones.80

Clinical features include right upper quadrant pain,jaundice, and ascites. Doppler ultrasound is veryimportant in diagnosis. The treatment is anticoagulationat the onset, identification of procoagulant causes, andshunting, or liver transplantation in extreme cases.

Liver transplantationBecause of the success of liver transplantation, youngpatients who have been successfully grafted can becomepregnant. Pregnancy should be deferred for 1 year afterliver transplantation, which allows lower doses ofimmunosuppression and more stable graft function.Pregnancy in this group should be managed inspecialised centres. 70% of women after livertransplantation will deliver a healthy baby,104 althoughpregnancy might pose problems, such as an increasedrisk of gestational diabetes and pre-eclampsia.104,105Caesarean deliveries are also more likely in this group:3563% versus 23% in the general population within theUK.106108 Commonly used drugs such as tacrolimus,mycophenalate mofetil, prednisolone, azathioprine, andciclosporin all carry a risk of teratogenicity. Prematurity

and low birthweights (


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mother and fetus. Liver disease in pregnancy can present

with subtle changes in liver biochemical profile or with ful-minant hepatic failure. These disorders are complex andmight need to be managed by experienced physicians inspecialised centres. Maternal and fetal survival has im-proved because of better understanding of the pathogene-sis of these disorders and higher standards of clinical care.

Contributors

DJ wrote and edited the report. AJ provided obstetric expertise, andreviewed and edited the report. RHW reviewed and edited the report.AQ reviewed and edited the report, and provided histopathologicalexpertise. MAH wrote, edited, and helped to supervise the preparation ofthe report.

Conflicts of interest

We declare that we have no conflicts of interest.

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